Peripherally acting opioid compounds

ABSTRACT

The invention relates to a compound of Formula I, II, III, IV or a pharmaceutically acceptable ester or prodrug thereof:

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/537,544, filed Jun. 29, 2012 which claims the benefit of U.S.Provisional Application No. 61/502,721, filed on Jun. 29, 2011. Theentire teachings of the above applications are incorporated herein byreference.

TECHNICAL FIELD

This invention relates to peripherally acting opioid compounds useful asopioid receptor modulators.

BACKGROUND OF THE INVENTION

Opiates have been the subject of intense research since the isolation ofmorphine in 1805, and thousands of compounds having opiate oropiate-like activity have been identified. Many opioidreceptor-interactive compounds including those used for producinganalgesia (e.g., morphine) and those used for treating drug addiction(e.g., naltrexone) have been employed in human therapy. Almost alltherapeutically useful opioids in the benzomorphan and morphinan classeshave a phenolic hydroxyl group (OH) at a position which is numbered “8”in the numbering system used for 2,6-methano-3-benzazocines [e.g.,cyclazocine and EKC (ethylketocyclazocine)] and which is numbered “3” inthe numbering system used for morphinans (e.g., morphine). When the3-hydroxyl group is replaced by a number of small, polar, neutralresidues, such as carboxamide and thiocarboxamide groups, the adjacent4-position may be substituted with a hydroxyl to produce compounds withhigh affinity for the opioid receptor. (Wentland M: WO 2009023567; WO2010011619; U.S. Pat. No. 6,784,187; U.S. Pat. No. 6,887,998; U.S. Pat.No. 7,262,298; U.S. Pat. No. 7,557,119). Compounds that bind to suchreceptors are likely to be useful in the treatment of diseases modulatedby opiate receptors for example, mediating analgesia, combating drug andopioid addiction, alcohol addiction, drug overdose, mental illness,compulsive behavior, bladder dysfunctions, neurogenic bladder,interstitial cystitis, urinary incontinence, premature ejaculation,inflammatory pain, peripherally mediated and neuropathic pain, cough,convulsions, lung edema, diarrhea, constipation, pruritus, cardiacdisorders, cardioprotection, and cognitive, respiratory depression,irritable bowel syndrome and gastro-intestinal disorders,immunomodulation, binge eating, anorexia, hyperalgesia, dyskinesia,anti-psychotic induced weight gain and as anti-tumor agents.

The potent antinociceptive actions of classical opioids such as morphineare traditionally considered to be predominantly mediated centrallythrough an action at the supraspinal or spinal level. Antinociceptiveeffects have also been demonstrated to result after local application ofopioids in the periphery, for example, in mouse writhing, and in ratmodels of inflammation or neuropathic pain. These effects have beenattributed to opioid induced actions mediated by peripheral opioidreceptors. Neuroanatomical, molecular and electro-physiological studieshave shown that such receptors are expressed on peripheral terminals ofsensory neurons where they can modulate both afferent and efferentneuronal functions, resulting in antinociception. (Furst et al., J.Pharmacol Exp Ther. (2005) 312(2), 609-18). In addition, opioidreceptors have been found on immune cells known to migrate into enterictissues and the epithelial cells lining the gastrointestinal tract. Assuch, opioids interacting with peripheral opioid receptors withoutcrossing the blood-brain barrier might be used as potent analgesics andare devoid of centrally mediated side effects are of interest intreating opioid mediated diseases.

SUMMARY

The invention relates to compounds of Formula I, II, III, IV or apharmaceutically acceptable ester or prodrug thereof:

-   Wherein:-   u is 0, 1 or 2;-   t is 0, 1, 2, 3, 4, 5, 6, or 7;-   X is S or O;-   Y^(⊖) is a pharmaceutically acceptable counterion;-   R₁ is selected from aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl or substituted heterocyclyl;-   Each R₂, R₃, R₄, R₆, R₈, and R₁₁ is independently selected from    absent, hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀,    —C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,    alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,    dialkylamino, substituted dialkylamino, alkylthio, substituted    alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic,    substituted aliphatic, aryl, substituted aryl, heterocyclyl or    substituted heterocyclyl; or alternatively, two of R₂, R₃, R₄, R₈    and R₁₁ together with the atoms they are attached to form one or two    optionally substituted rings; alternatively R₂ and R₃ together with    the carbon they are attached to form a C═X group or a vinyl group;    alternatively, two R₁₁ groups together with the carbon atom to which    they are attached form a C═X or a vinyl group;    -   wherein each R₂₀ and R₂₁ is independently selected from absent,        hydrogen, halogen, -alkyl, substituted alkyl, aryl or        substituted aryl;-   R₅ is alkyl, substituted alkyl, aryl or substituted aryl;-   R₇ is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;-   R₉ is selected from hydrogen, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;-   R₁₀ is selected from —[C(R₂₃)(R₂₄)]_(m)—R₂₅;    -   Wherein m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;    -   Each R₂₃ and R₂₄ is independently selected from hydrogen,        halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀,        —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,        alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,        dialkylamino, substituted dialkylamino, alkylthio, substituted        alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic,        substituted aliphatic, aryl, substituted aryl, heterocyclyl or        substituted heterocyclyl; and,-   R₂₅ is heterocyclyl, substituted heterocyclyl, aryl substituted with    heteroaryl or aryl substituted with heterocyclyl.

The invention further relates to a method of treating a disease ordisorder by modulating the activity of an opioid receptor comprising thestep of administering a compound of Formula I to a subject in needthereof.

DESCRIPTION OF FIGURES

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1: The administration (intra-plantar) of Compound 4 produced adose-dependent reversal of CFA-induced weight bearing deficits at 3, 10and 30 μg/paw.

FIG. 2: The administration (intra-plantar) of morphine produced adose-dependent reversal of CFA-induced weight bearing deficits at 3, 10and 30 μg/paw.

FIG. 3: The antinociceptive properties of subcutaneous (SC)administration of Compound 4 were assessed at doses of 10, 30, and 100mg/kg in the rat hot plate test of antinociception.

FIG. 4: Subcutaneous administration of Compound 4 produced adose-dependent reversal of formalin-induced events in a formalin modelof pain.

FIG. 5: Administration (intraperitoneal) of Compound 4 blocked aceticacid induced writhing in a dose-dependent manner in an acetic-acidinduced writhing model of inflammatory pain.

DETAILED DESCRIPTION

In one embodiment, the invention relates to a compound of Formula I, II,III, IV or a pharmaceutically acceptable ester or prodrug thereof:

-   Wherein:-   u is 0, 1 or 2;-   t is 0, 1, 2, 3, 4, 5, 6, or 7;-   X is S or O;-   Y^(⊖) is a pharmaceutically acceptable counterion;-   R₁ is selected from aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl or substituted heterocyclyl;-   Each R₂, R₃, R₄, R₆, R₈, and R₁₁ is independently selected from    absent, hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀,    —C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,    alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,    dialkylamino, substituted dialkylamino, alkylthio, substituted    alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic,    substituted aliphatic, aryl, substituted aryl, heterocyclyl or    substituted heterocyclyl; or alternatively, two of R₂, R₃, R₄, R₈    and R₁₁ together with the atoms they are attached to form one or two    optionally substituted rings; alternatively R₂ and R₃ together with    the carbon they are attached to form a C═X group or a vinyl group;    alternatively, two R₁₁ groups together with the carbon atom to which    they are attached form a C═X or a vinyl group;    -   wherein each R₂₀ and R₂₁ is independently selected from absent,        hydrogen, halogen, -alkyl, substituted alkyl, aryl or        substituted aryl;-   R₅ is alkyl, substituted alkyl, aryl or substituted aryl;-   R₇ is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;-   R₉ is selected from hydrogen, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;-   R₁₀ is selected from —[C(R₂₃)(R₂₄)]_(m)—R₂₅;    -   Wherein m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;    -   Each R₂₃ and R₂₄ is independently selected from hydrogen,        halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀, —C(O)OR₂₀,        —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,        alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,        dialkylamino, substituted dialkylamino, alkylthio, substituted        alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic,        substituted aliphatic, aryl, substituted aryl, heterocyclyl or        substituted heterocyclyl; and,    -   R₂₅ is heterocyclyl, substituted heterocyclyl, aryl substituted        with heteroaryl or aryl substituted with heterocyclyl.

The invention further relates to a method of treating a disease ordisorder by modulating the activity of an opioid receptor(s) comprisingthe step of administering a compound of Formula I or II to a subject inneed thereof.

In a preferred embodiment, the invention relates to a compound ofFormula V, VI, or a pharmaceutically acceptable ester or prodrugthereof:

The invention further relates to a method of treating a disease ordisorder mediated by opioid receptor comprising the step ofadministering a compound of Formula II or a pharmaceutically acceptableester or prodrug thereof to a subject in need thereof.

In a more preferred embodiment, the invention relates to a compound ofFormula I or II or a pharmaceutically acceptable ester or prodrugthereof, wherein R₁₀ is selected from Table A:

TABLE A

-   Wherein s is 0, 1, 2, or 3;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   q is 0, 1, 2, 3, 4, or 5;-   Each R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, and R₁₀₅ is independently    selected from hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —C(O)R₂₀,    —C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃, acyl,    alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,    dialkylamino, substituted dialkylamino, substituted or unsubstituted    alkylthio, substituted or unsubstituted alkylsulfonyl, optionally    substituted aliphatic, optionally substituted aryl, heterocyclyl or    substituted heterocyclyl.

In a preferred embodiment, the invention relates to a compound or apharmaceutically acceptable ester or prodrug thereof, selected fromTable B:

TABLE B No Compound  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12.

13.

14.

15.

16.

In a preferred embodiment, the invention relates to a compound selectedfrom Table B, wherein R₁₀ is selected from Table A. In a more preferredembodiment, the invention relates to a compound selected Table B,wherein R₁₀ is selected from Table A and R₉ is hydrogen.

In a preferred embodiment, R₁ is selected from —(CH₂)_(a)-c-C₃H₅,—(CH₂)_(a)-c-C₄H₇, —(CH₂)_(a)-c-C₅H₉, —(CH₂)_(a)—CH═CH₂, —CH₃,—CH₂—CH₂-phenyl or —(CH₂)_(a)—CH═C(CH₃)₂ wherein a is independently 0,1, 2 or 3.

In a preferred embodiment, the invention relates to a compound selectedfrom Table C or a pharmaceutically acceptable ester or prodrug thereof:

TABLE C No Compound  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

In a more preferred embodiment, the invention relates a method oftreating opioid receptor mediated disease or disorder comprising thestep of administering a compound of Table C to a subject in needthereof. In one embodiment, the invention relates to the treatment ofpain comprising the administration of a compound of Formula I or II to asubject in need thereof. In one embodiment, the pain is selected frominflammatory pain, centrally mediated pain, peripherally mediated pain,visceral pain, structural related pain, cancer pain, soft tissue injuryrelated pain, progressive disease related pain, neuropathic pain andacute pain from acute injury, acute pain from trauma, acute pain fromsurgery, chronic pain from headache, chronic pain from neuropathicconditions, chronic pain from post-stroke conditions and chronic painfrom migraine. In one embodiment, the pain is associated withosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite, spider bite, insect sting,neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis,rhinitis, contact dermatitis/hypersensitivity, itch, eczema,pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, post-operative ileus, cholecystitis,postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain,reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgiaparesthetica, burning-mouth syndrome, post-herpetic neuralgia,trigeminal neuralgia, cluster headache, migraine headache, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy, opticneuritis, postfebrile neuritis, migrating neuritis, segmental neuritis,Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranialneuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainousneuralgia, idiopathic neuralgia, intercostals neuralgia, mammaryneuralgia, Morton's neuralgia, nasociliary neuralgia, occipitalneuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, vidian neuralgia, inflammatory bowel disease,irritable bowel syndrome, sinus headache, tension headache, labor,childbirth, menstrual cramps, and cancer.

In one embodiment, the invention relates to the treatment of painassociated with arthritis. In one embodiment, arthritis is selected fromrheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis, juvenile arthritis, scapulohumeral periarthritis.

Compounds of the instant application show good binding affinities toopiate receptors. Some of the compounds of the invention show agonistactivity based on their ability to induced GTPγS binding at one or moreof the opiate receptors (MOR, DOR, KOR or NOP). As such, the compoundsof the instant application are useful in the treatment of diseasesmodulated by opioid receptor activation; for example: mediatinganalgesia, combating drug and opioid addiction, alcohol addiction, drugoverdose, mental illness, bladder dysfunctions, neurogenic bladder,interstitial cystitis, urinary incontinence, premature ejaculation,inflammatory pain, neuropathic pain, cough, lung edema, diarrhea,pruritus, cardiac disorders, cardioprotection, and cognitive,respiratory depression, irritable bowel syndrome and gastro-intestinaldisorders, immunomodulation, and anti-tumor agents.

The compounds of the present invention may be used in methods to treatdiseases where ligand binding primarily to the μ opioid receptor isdesired. Compounds of interest may also bind to κ and δ receptors. Theopioid receptors may be located in the located outside central nervoussystem in the periphery and located on nerve cells, immune cells, glialcells, or epithelial cells. If compounds are directly injected into thecentral nervous system (CNS) they would bind to opioid receptors there.

In one embodiment, the compounds are opioid receptor agonist. In anotherembodiment, the compounds are opioid antagonists preventing or treatinga condition or disease caused by an opioid (either endogenous orexogenous). In another embodiment, compounds can function broadly inmodulating opioid receptor activity having a combination of agonist andantagonist properties at the μ, κ, and δ receptors. In yet anotherembodiment the compounds of the invention preferably do notsubstantially cross the blood-brain barrier.

The compounds of the present invention may be used in methods toantagonize opioid receptors, particularly where undesirable symptoms orconditions are side effects of administering exogenous opioids.Furthermore, the compounds of the invention may be used to treatpatients having disease states that are ameliorated by binding to opioidreceptors or in any treatment wherein temporary suppression ormodulation of the μ opioid receptor signaling is desired.

Such symptoms, conditions or diseases include the complete or partialantagonism of opioid-induced sedation, confusion, respiratorydepression, euphoria, dysphoria, hallucinations, pruritus (itching),increased biliary tone, increased biliary colic, and urinary retention,ileus, emesis, and addiction liability; prevention or treatment ofopioid and cocaine dependence; rapid opioid detoxification; treatment ofalcoholism; treatment of alcoholic coma; detection of opioid use orabuse (pupil test); treatment of eating disorders; treatment of obesity;treatment of post-concussional syndrome; adjunctive therapy in septic,hypovolemic or endotoxin-induced shock; potentiation of opioid analgesia(especially at ultra-low doses); reversal or prevention of opioidtolerance and physical dependence (especially at ultra-low doses);prevention of sudden infant death syndrome); treatment of dyskinesia;treatment of metabolic diseases, including Type 1 and 2 diabetes;treatment of the endocrine system (including increased release ofluteinizing hormone, treatment of infertility, increasing number ofmultiple births in animal husbandry, and male and female sexualbehavior); treatment of the immune system and cancers associated withbinding of the opioid receptors; treatment of anxiolysis; treatment ofdiuresis; treatment and regulation of blood pressure; treatment oftinnitus or impaired hearing; treatment of epilepsy; treatment ofcachexia; treatment of general cognitive dysfunctions; and treatment ofkleptomania.

The compounds of the present invention may also be used as cytostaticagents, as antimigraine agents, as immunomodulators, asimmunosuppressives, as antiarthritic agents, as antiallergic agents, asvirucides, to treat diarrhea, as antischizophrenics, as uropathicagents, as antitussives, as antiaddictive agents, as anti-smokingagents, to treat alcoholism, as hypotensive agents, to treat and/orprevent paralysis resulting from traumatic ischemia, generalneuroprotection against ischemic trauma, as adjuncts to nerve growthfactor treatment of hyperalgesia and nerve grafts, as anti-diuretics, asstimulants, as anti-convulsants, or to treat obesity. Additionally, thepresent compounds may be used in the treatment of Parkinson's disease asan adjunct to L-dopa for treatment dyskinesia associated with the L-dopatreatment.

In certain embodiments, the compounds of the invention may be used inmethods for preventing or treating gastrointestinal dysfunction,including, but not limited to, irritable bowel syndrome, opioid-boweldysfunction, colitis, post-operative and opioid-induced emesis (nauseaand vomiting), decreased gastric motility and emptying, inhibition ofsmall and/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, and delayed absorptionof orally administered medications or nutritive substances.

In one embodiment, the compositions of the invention may furthercomprise one or more compounds that may be designed to enhance theanalgesic potency of the opioid and/or to reduce analgesic tolerancedevelopment. Such compounds include, for example, dextromethorphan orother NMDA antagonists (Mao, M. J. et al., Pain, 1996, 67, 361),L-364,718 and other CCK antagonists (Dourish, C. T. et al., Eur. J.Pharmacol., 1988, 147, 469), NOS inhibitors (Bhargava, H. N. et al.,Neuropeptides, 1996, 30, 219), PKC inhibitors (Bilsky, E. J. et al., J.Pharmacol. Exp. Ther., 1996, 277, 484), and dynorphin antagonists orantisera (Nichols, M. L. et al., Pain, 1997, 69, 317). The disclosuresof each of the foregoing documents are hereby incorporated herein byreference, in their entireties.

In one embodiment, the compounds of the invention can be used in methodsfor preventing or treating post-operative or opioid-induced ileus. Inanother embodiment, the compounds of the invention can be used as ananalgesics, anesthetics, anti-pruritics, anti-diarrheal agents,anti-convulsants, anti-tussives, and/or anorexics.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted.

In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may include alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, and substituted or unsubstituted cycloalkyl groups as describedherein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆)alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”). Otherpreferred alkyl groups comprise at about 1 to about 8 carbon atoms(“C₁-C₈”) such as about 1 to about 6 carbon atoms (“C₁-C₆”), or such asabout 1 to about 3 carbon atoms (“C₁-C₃”). Examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl and n-hexylradicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkenyl radicals are “lower alkenyl” radicals having two to about tencarbon atoms (“C₂-C₁₀”) such as ethenyl, allyl, propenyl, butenyl and4-methylbutenyl. Preferred lower alkenyl radicals include 2 to about 6carbon atoms (“C₂-C₆”). The terms “alkenyl”, and “lower alkenyl”,embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkynyl radicals are “lower alkynyl” radicals having two to about tencarbon atoms such as propargyl, 1-propynyl, 2-propynyl, 1-butyne,2-butynyl and 1-pentynyl. Preferred lower alkynyl radicals include 2 toabout 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means an aromatic systemcontaining one, two or three rings wherein such rings may be attachedtogether in a pendent manner or may be fused. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanefuranyl, quinazolinyl, pyridyl and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl”correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “compound” “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount” with respect to the subjectmethod of treatment, refers to an amount of the subject compound which,when delivered as part of desired dose regimen, brings about managementof the disease or disorder to clinically acceptable standards.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, hetoerarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the formulas herein with proper valency.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described herein, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques, which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

Berge, et al. describes pharmaceutically acceptable salts in detail inJ. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts e.g.,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid or malonic acid or by using othermethods used in the art such as ion exchange. Other pharmaceuticallyacceptable salts include, but are not limited to, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion. Combinations ofsubstituents and variables envisioned by this invention are only thosethat result in the formation of stable compounds. The term “stable”, asused herein, refers to compounds which possess stability sufficient toallow manufacture and which maintains the integrity of the compound fora sufficient period of time to be useful for the purposes detailedherein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc., delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired bridged macrocyclic products of the presentinvention. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G., S. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxy protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.,by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from the injection site. This may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution, which, in turn, maydepend upon crystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplished bydissolving or suspending the drug in an oil vehicle. Injectable depotforms are made by forming microencapsule matrices of the drug inbiodegradable polymers such as polylactide or polylactide-co-glycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid; b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate; h) absorbents such as kaolinand bentonite clay; and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

In one embodiment, administration of the microparticles comprisingiloprost or another pharmaceutical agent to be administered in additionto iloprost provides local or plasma concentrations sustained atapproximately constant values over the intended period of release (e.g.,up to 2 to 24 hours, to enable dosing once, twice, three times, fourtimes or more than four times per day). The microparticle formulationsmay allow patients to take treatments less frequently, and to receivemore prolonged and steadier relief.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluents such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

The total daily dose of the compounds of this invention administered toa subject in single or in divided doses can be in amounts, for example,from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kgbody weight. Single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 1 mg to about 200 mg of thecompound(s) of this invention per day or per weekly or per bi-weekly insingle or multiple doses.

Dosing schedules may be adjusted to provide the optimal therapeuticresponse. For example, administration can be one to three times dailyfor a time course of one day to several days, weeks, months, and evenyears, and may even be for the life of the patient. Practicallyspeaking, a unit dose of any given composition of the invention oractive agent can be administered in a variety of dosing schedules,depending on the judgment of the clinician, needs of the patient, and soforth. The specific dosing schedule will be known by those of ordinaryskill in the art or can be determined experimentally using routinemethods. Exemplary dosing schedules include, without limitation,administration five times a day, four times a day, three times a day,twice daily, once daily, every other day, three times weekly, twiceweekly, once weekly, twice monthly, once monthly, and so forth.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

The morphinan compounds according to the present invention may besynthesized employing methods taught, for example, in U.S. Pat. No.5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No. 5,159,081, and U.S.Pat. No. 5,270,328. The optically active and commercially availablenaltrexone that can be employed as starting material in the synthesis ofsome of the compounds of the invention may be prepared by the generalprocedure taught in U.S. Pat. No. 3,332,950.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Synthesis Of Heterocyclic Bi-Aryls Example 1 Synthesis of tert-butyl4-bromophenethylcarbamate

Bromophenethylamine (50 g, 250 mmol) and triethylamine (105 mL, 750mmol) were stirred in dichloromethane (DCM; 1.5 L), and cooled to 0° C.Boc anhydride (82 g, 375 mmol) was added and the reaction mixturestirred at room temperature overnight. The reaction mixture was washedwith water (1 L), brine (500 mL), dried (MgSO₄) and concentrated to givean orange oil. The crude residue was crystallized from hexane (250 mL)to give a white solid, tert-butyl 4-bromophenethylcarbamate (39.85 g,133 mmol, 53%).

Example 2 Synthesis of tert-butyl4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate

Industrial methylated spirits (IMS; 15 mL) and water (5 mL) weredegassed thoroughly. tert-butyl 4-bromophenethylcarbamate (1.08 g, 3.63mmol), sodium carbonate (1.54 g, 14.52 mmol), palladium tetrakis (0.42g, 0.36 mmol) and 2,4-dimethoxy-5-pyrimidinylboronic acid (1.00 g, 5.44mmol) were added and the reaction mixture heated to 90° C. for 18 hours.No starting material was observed by LCMS. Water (100 ml) and ethylacetate (300 ml) were added and the organic layer separated. The organiclayer was washed with water (100 ml), dried (MgSO₄) and concentrated togive a yellow oil. The crude residue was subject to columnchromatography (20 to 60% ethyl acetate/hexane) to give a yellow oil,tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl) phenethylcarbamate, whichcrystallized on standing (1.18 g, 3.28 mmol, 91%).

Example 3 Synthesis of5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride

To tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl) phenethylcarbamate (0.5 g,1.39 mmol) was added aqueous hydrochloric acid (6M, 15 mL) and thereaction mixture stirred at reflux for 4 hours. No starting material wasobserved by LCMS. The precipitate was filtered, washed with water (5 mL)and dried under reduced pressure (50° C.) to give a pale yellow solid,5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride(0.32 g, 1.35 mmol, 86%).

Example 4 Synthesis of tert-Butyl4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate

IMS (50 mL) and water (16 mL) were degassed thoroughly. tert-Butyl4-bromophenethylcarbamate (3.52 g, 11.7 mmol), sodium carbonate (5.0 g,46.9 mmol), palladium tetrakis (1.35 g, 1.2 mmol) and1-benzyl-1H-pyrazole-4-boronic acid pinacol ester (5.0 g, 17.6 mmol)were added and the reaction mixture heated to 90° C. overnight. Thereaction was partitioned between ethyl acetate (500 mL) and water (250mL) and brine (250 mL), then dried (MgSO₄). Filtration and removal ofthe solvent gave the crude residue which was subject to columnchromatography (50% ethyl acetate/heptane) to give tert-butyl4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (4.2 g, 11.1 mmol,95% yield).

Example 5 Synthesis of 2-(4-(1-Benzyl-1H-pyrazol-4-yl)phenyl)ethanaminehydrochloride

To tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (4.2g, 11.1 mmol) was added HCl/dioxane (approximately 4M, 100 mL). After 5minutes, the reaction mixture had stopped stirring and a further 50 mLHCl/dioxane was added. The reaction was stirred at room temperature for6 hours. The solvent was removed under reduced pressure giving2-(4-(1-benzyl-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride as ayellow solid (4.0 g, 11.1 mmol, 100% yield).

Example 6 Synthesis of tert-Butyl4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate

IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g,436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridineboronoic acid (25.0 g, 163 mmol) were added and the reaction mixtureheated to 90° C. for 18 hours. The reaction was cooled to roomtemperature, filtered and the residue washed with IMS (100 mL) and ethylacetate (1 L). The filtrate was washed with water (500 mL), dried(MgSO₄) and concentrated to give a brown solid. The crude residue wassubject to column chromatography (0 to 1.5% MeOH in DCM) to give a whitesolid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate(20.95 g, 63.8 mmol, 58% yield).

Example 7 Synthesis of 5-(4-(2-Aminoethyl)phenyl)pyridin-2(1H)-onehydrochloride

To tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (10.25g, 31.0 mmol) was added aqueous hydrochloric acid (6M, 220 mL) and thereaction mixture stirred at reflux overnight. The reaction was cooled toroom temperature and the precipitate was filtered, washed with water (5mL) and dried under reduced pressure (50° C.). The acidic solution wasconcentrated under reduced pressure and the resultant solid combinedwith the filtered solid to give5-(4-(2-aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride (7.80 g, 31.0mmol, 100% yield).

Synthesis of Opioids

Example 8 Synthesis of Compound 4

To a solution of the crude Compound 12 (52 g) in acetic acid (1 L) at90° C. was added concentrated HCl (35 mL). To this was then added zincpowder (64 g, 0.98 mol) over 35 minutes and after complete addition afurther portion of concentrated HCl (40 mL) was added over 5 minutes. Tothe reaction mixture was then added a second portion of zinc powder (64g, 0.98 mol) over 1 hour. After 30 minutes a third portion of zincpowder (32 g, 0.49 mol) and the reaction heated a further 1 hour. Thereaction was cooled to ˜60° C. and filtered and the zinc residue washedwith warm acetic acid. The filtrate was concentrated under reducedpressure and the residue diluted with concentrated ammonia (1 L) and2-methyltetrahydrofuran (1 L) and waster (0.5 L). The mixture wasstirred for 10 minutes and the liquids decanted from the brown gum. Thegum was washed with water and all the liquid combined. The organic phasewas separated, dried over MgSO₄ and combined with the brown gum andconcentrated under reduced pressure. The resulting residue was dissolvedin dichloromethane/methanol (8:2) and columned on a short plug of silicaeluting with dichloromethane/methanol (8:2) and thendichloromethane/methanol/triethylamine (16:3:1). The product containingfractions were evaporated and re-columned eluting withdichloromethane/methanol (9:1) and then dichloromethane/(16%NH₃/methanol) (9:1). The product obtained from this was then furtherpurified by prep. HPLC to give Compound 4; LC/MS 545 (M+H)⁺;NMR(DMSO-D₆): 1.30-2.10 (6H, m), 2.12-3.05 (11H, m), 3.10-3.60 (2H, m),4.04 (1H, bs), 4.58 (1H, s), 6.42 (1H, bs), 7.19 (2H, d), 7.40-7.60 (5H,m), 10.45 (3H, bs).

Example 9 Synthesis of Compounds 13 and 14

A solution of (5a)-N-[2-(4-bromophenyl)ethyl]-14-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-3-carboxamide(1.7 g, 3.3 mmol) in denatured ethanol (15 mL) was degassed with argonfor 20 min and then Na₂CO₃ (1.4 g, 13.3 mmol),2,4-dimethoxypyrimidin-5-ylboronic acid (0.92 g, 5.0 mmol), degassedwater (5 mL) and Pd(PPh₃)₄ (0.38 g, 0.33 mmol) added. The reaction wassealed and heated in a microwave reactor at 120° C. for 25 min. Thereaction was concentrated to ˜10 mL, diluted with dichloromethane (50mL) and washed with water (40 mL). The organic phase was dried overMgSO₄, filtered and evaporated. The residue was further purified onsilica eluting with dichloromethane to methanol/dichloromethane (1:9).The product containing fraction were re-purified on silica eluting withdichloromethane/ethyl acetate (9:1) to dichloromethane/ethylacetate/methanol (8:1:1) to give the Compound 13 (1.38 g, 73%) as ayellow oil.

To a mixture of Compound 13 (0.70 g, 1.2 mmol) and sodium iodide (1.33g, 4.9 mmol) in anhydrous acetonitrile (8 mL) was addedchlorotrimethylsilane (0.63 mL, 4.9 mmol) and the reaction mixturestirred for 5 h. The reaction mixture was diluted with 5% aqueous sodiumsulfite (5 mL) and water (10 mL) and then made basic with saturatedaqueous sodium carbonate. This was extracted with twice withdichloromethane (80 mL) and once with ethyl acetate (50 mL). The organiclayers were combined and evaporated to give a yellow solid. This waspartially dissolved in 2M HCl and the insoluble material was filteredoff with celite. The aqueous phase was made basic with saturated sodiumcarbonate and the resulting white solid filtered and dried under vacuum.This was then purified on silica eluting with dichloromethane/methanol(9:1) to give Compound 14 (197 mg). Compound 14 was dissolved indichloromethane (5 mL) and 4M HCl in diethyl ether (40 mL) added. Themixture was stirred for 2.5 h and evaporated to give the chloride saltof Compound 14 ((0.21 g, 29%) as a white solid; LC/MS 543 (M+H)⁺;NMR(DMSO-D₆): 1.40-1.57 (2H, m), 1.90-2.01 (1H, m), 2.10-2.20 (1H, m),2.58-2.70 (1H, m), 2.75-2.92 (5H, m), 2.92-3.15 (3H, m), 3.30-3.65 (4H,m), 5.31 (1H, s), 6.79 (1H, s), 6.93 (1H, d), 7.26 (2H, d), 7.44 (2H,d), 7.55 (1H, d), 7.60-7.70 (2H, m), 9.36 (1H, bs), 11.10 (1H, bs),11.20 (1H, bs).

Example 10 Synthesis of Compound 10

Oxymorphone triflate (3.0 g, 7.0 mmol) was stirred in degassed DMSO (40mL). N-hydroxysuccinimide (1.60 g, 13.9 mmol) was added followed bytriethylamine (1.94 mL, 13.9 mmol), palladium acetate (156 mg, 0.7 mmol)and xantphos (402 mg, 0.7 mmol). The reaction mixture was stirred at 70°C. under an atmosphere of CO overnight. Further palladium acetate (1.04g, 4.61 mmol) and xantphos (2.68 g, 4.63 mmol) were added and thereaction mixture heated 6 hours 70° C. under an atmosphere of CO. Themixture was allowed to return to room temperature before the addition of4-(4-(2-aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride (2.0 g, 8.0mmol) and triethylamine (2 mL, 14.3 mmol). The reaction was stirred for1 hour before removal of the DMSO under reduced pressure. The residuewas subject to column chromatography (0 to 5% MeOH (NH₃) in DCM). Theisolated residue was found to still contain DMSO and was portionedbetween DCM (500 mL) and water (250 mL). The aqueous phase was extracteda further five times until the product was completely extracted. Theorganic phases were combined and the solvent removed under reducedpressure giving(4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(Compound-15; 1.2 g, 2.3 mmol, 33% yield).

To a solution of the crude Compound-15 (52 g) in acetic acid (55 mL) wasadded zinc powder (3.03 g, 45.8 mmol) followed by concentratedHCl_((aq)) (2 mL). The reaction was heated at 90° C. for 2 hours. Thereaction mixture was allowed to cool to 60° C. and filtered. The zincresidue was washed with further acetic acid (30 mL). The combined aceticacid solutions were concentrated under reduced pressure. The residue wasbasified with ammonium hydroxide solution (28%) and extracted withMe-THF (2×250 mL). The organic phase was dried (MgSO₄), filtered, andthe solvent removed under reduced pressure. The crude product wassubject to column chromatography (0 to 5% MeOH (NH₃) in DCM) followed byprep-HPLC to give Compound 10(4,14-dihydroxy-N-{2-[4-(2-hydroxypyridin-4-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide)(378 mg, 0.72 mmol, 31% yield) as a white solid; LC/MS 528 (M+H)⁺;NMR(DMSO-D₆): 533-20-7_1H-3.jdf: 1.45 (1H, d), 1.58-2.10 (4H), 1.8 (3H,s), 2.19-2.38 (1H, m), 2.40-3.10 (10H, m), 3.78 (1H, d), 4.68 (1H, bs),6.46 (1H, dd), 6.53 (1H, s), 6.61 (1H, d), 7.31 (2H, d), 7.39 (1H, d),7.53 (1H, d), 7.60 (2H, d), 8.96 (1H, bs).

Example 11 Synthesis of Compound 7

To an ice cold solution of(4a′S,7a′R)-9′-(benzyloxy)-3′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-4a′H-spiro[1,3-dioxolane-2,7′-[4,12]methano[1]benzofuro[3,2-e]isoquinolin]-4a′-ol(10 g, 23 mmol) in DMF (100 mL) was added portionwise sodium hydride(4.6 g, 115 mmol). The mixture was stirred cold for 2 hours then methyliodide (2.9 mL, 45.9 mmol) was added in one portion. The reaction waswarmed to room temperature and stirred overnight. The mixture was pouredinto water (500 mL) and extracted into DCM (2×500 mL). The organic layerwas washed with water (3×300 mL) and brine (300 mL), dried (MgSO₄),filtered and concentrated to give the crude product. The product waspurified by silica column chromatography (eluting 0-10% ammonia/methanolin DCM) to give the product(4R,4aS,7aR,12bS)-9-(benzyloxy)-4a-methoxy-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]as a viscous yellow oil (7.3 g, 71% yield).

To a solution of(4R,4aS,7aR,12bS)-9-(benzyloxy)-4a-methoxy-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane](7.3 g, 16.2 mmol) in MeOH (75 mL) was added conc. HCl (50 mL). Themixture was refluxed for 5 hours then cooled with an ice bath.Concentrated ammonia (25%) was added until pH 8 was reached. The mixturewas concentrated and the residues stirred with 10% MeOH/DCM (1 L)overnight. The mixture was filtered and the liquors concentrated to give(4R,4aS,7aR,12bS)-9-hydroxy-4a-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-oneas a dark red oil (5.3 g, quantitative yields).

A mixture of(4R,4aS,7aR,12bS)-9-hydroxy-4a-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(5.1 g, 16.2 mmol), N-Phenylbis(trifluoromethanesulfonamide) (6 g, 16.7mmol), triethylamine (6.8 mL, 48.5 mmol) and DCM (80 mL) was stirred atroom temperature overnight. The mixture was concentrated under reducedpressure to give the crude product still containing triflating reagent.This was dissolved in 4:1 mixture of ethyl acetate/hexane (200 mL) andwashed with water (5×150 mL). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure to give the product(4R,4aS,7aR,12bS)-4a-methoxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonateas a brown oil (5.9 g, 81% yield). Compounds 7 and 16 were synthesizedfrom the above intermediate in a similar procedure as in the synthesisof compounds 10 and 15.

Example 12 Synthesis of Compound 11

A mixture of(5a)-N-[2-(4-bromophenyl)ethyl]-14-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-3-carboxamide(1) (10 g, 19.6 mmol), denatured ethanol (300 mL), zinc powder (28 g,0.43 mol) and ammonium chloride (34.5 g, 0.65 mol) was heated at refluxfor 30 min and then cooled to ˜40° C. The reaction mixture was filteredthrough celite and washed with denatured ethanol (300 mL, 40° C.). Thevolatiles were removed under vacuum and the residue partitioned betweendichloromethane (200 mL) and 2% aqueous ammonia (300 mL). The aqueousphase was further extracted with dichloromethane (2×200 mL) and thecombined organics were dried over MgSO₄ and evaporated. The residue waspurified on silica eluting with dichloromethane/methanol (95:5 to 9:1)to giveN-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide(2) (7.95 g, 79%) as a brown solid.

To a degassed mixture of ethanol and water (4:1, 20 mL) was added2-methoxypyrimidin-5-ylboronic acid (0.67 g, 4.4 mmol), Na₂CO₃ (1.24 g,11.7 mmol) andN-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide(2) (1.5 g, 2.9 mmol). The reaction mixture was further degassed andthen Pd(PPh₃)₄ (0.32 g, 0.3 mmol) added. The reaction mixture was heatedin a microwave reactor at 120° C. for 25 min. and cooled. The reactionmixture was diluted with ethyl acetate (50 mL) and washed with 1:1brine/water (3×35 mL). The organic phase was dried over MgSO₄, filteredand evaporated. The resulting residue was further purified on silicaeluting with dichloromethane/methanol (9:1) to give4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide(3) (0.50 g, 32%) as a yellow foam.

A mixture of4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide(3) (0.5 g, 0.9 mmol) and pyridine hydrochloride (5 mL) was heated at150° C. for 6 h. The reaction mixture was cooled, basified withsaturated aqueous sodium bicarbonate and extracted with dichloromethane(3×40 mL). The aqueous phase was filtered and the collected brown solidwas combined with the organic washes and evaporated to dryness. Theresidue was purified on silica eluting with dichloromethane/methanol(9:1) to dichloromethane/16% NH₃ in methanol (9:1) to give4,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl]ethyl}morphinan-3-carboxamide(RDC6139) (0.15 g) as a white solid. This was dissolved indichloromethane/methanol (3:1, 20 mL) and maleic acid (32 mg, 1 eq)added. The reaction mixture was stirred for 4 h and then the volatilesremoved under vacuum at 40° C. The residue was freeze dried from waterto give Compound 114,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl]ethyl}morphinan-3-carboxamidemaleate salt (0.17 g, 98%) as a white solid; LC/MS 529 (M+H)⁺; NMR(D₂O):1.15-1.21 (4H, m), 1.49-1.60 (1H, m), 1.65-1.90 (3H, m), 2.10-2.22 (1H,m), 2.29-2.41 (1H, m), 2.50-2.72 (5H, m), 2.90-3.00 (1H, m), 3.18-3.40(3H, m), 3.45-3.60 (2H, m), 6.04 (2H, s), 6.95-7.05 (4H, m), 7.26 (1H,m), 8.11 (2H, bs).

Example 13 Synthesis of Compound 5

A mixture of Hydromorphone HCl (100 g, 0.31 mol),N-Phenylbis(trifluoromethanesulfonamide) (114 g, 0.32 mol),diisopropylethylamine (215 mL, 1.24 mol) and DCM (2 L) was stirred atroom temperature overnight. The mixture was concentrated under reducedpressure to give the crude product still containing triflating reagent.This was dissolved in 4:1 mixture of ethyl acetate/hexane (1 L) andwashed with water (6×1 L). The organic layer was dried (MgSO₄), filteredand concentrated under reduced pressure to give the product(4R,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonateas a white solid (120 g, 93% yield)(4R,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate(5 g, 11.98 mmol) was stirred in degassed DMSO (80 mL).N-hydroxysuccinimide (2.76 g, 23.96 mmol) was added followed bytriethylamine (3.3 mL, 23.96 mmol), palladium acetate (0.27 g, 1.2 mmol)and xantphos (0.69 g, 1.2 mmol). The reaction mixture was stirred at 70°C. under an atmosphere of CO overnight. The mixture was allowed toreturn to room temperature before the addition of5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (3.2g, 11.98 mmol) and triethylamine (3.3 mL, 23.96 mmol). The reaction wasstirred for 5 hours before removal of the DMSO under reduced pressure.The residue was stirred with DCM and filtered to give a brown solid,which was used as it was for the next step(4R,7aR,12bS)—N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenethyl)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(6 g, 79% crude yield).

To a solution of the crude(4R,7aR,12bS)—N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenethyl)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(5 g) in acetic acid (200 mL) was added zinc powder (12.6 g, 190 mmol)followed by concentrated HCl_((aq)) (7.5 mL). The reaction was heated at90° C. for 2.5 hours. Further zinc powder (47.6 g, 717 mmol) was addedportionwise over 24 hours. After cooling to room temperature, the zincsalts were removed by filtration and washed with further acetic acid (80mL). The combined acetic acid solutions were concentrated under reducedpressure. The residue was basified with ammonium hydroxide solution(28%) and extracted with Me-THF (3×500 mL). The organic phase was dried(MgSO₄), filtered, and the solvent removed under reduced pressure. Thecrude product purified by prep-HPLC to give Compound 5(4bS,9R)—N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenethyl)-4-hydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideas a white solid (0.89 g, 18% yield); LC/MS 529 (M+H)⁺; NMR(DMSO-D₆):1.25-1.50 (1H, m), 1.55-1.89 (4H, m), 1.98 (1H, d), 2.05-3.00 (7H, m),3.20-3.60 (6H, m), 4.01 (1H, d), 6.61 (1H, d), 7.19 (2H, d), 7.45 (2H,d), 7.50-7.64 (4H, m), 8.90 (1H, bs), 11.20 (1H, bs), 13.86 (1H, bs).

Example 14 Synthesis of Compound 2

A mixture of Noroxymorphone (40.0 g, 139.2 mmol), potassium hydrogencarbonate (27.9 g, 278.7 mmol), and (2-bromoethyl)benzene (47.6 mL,348.0 mmol) in DMF (750 mL) was heated at 70° C. overnight. The reactionmixture was cooled to room temperature, filtered, and concentrated underreduced pressure. The residue was partitioned between ethyl acetate (800mL) and water (500 mL). The organic phase was dried (MgSO₄), filteredand the solvent removed under reduced pressure. To the crude residue wasstirred with a mixture of 2N HCl_((aq)) (500 mL) and ethyl acetate (500mL). The resultant precipitate was isolated by filtration, washed withwater and dried (50° C.) giving(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-onehydrochloride (46.6 g, 109.0 mmol, 78% yield).

To a suspension of(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-onehydrochloride (46.6 g, 109.0 mmol) in DCM (1 L) was addeddiisopropylethylamine (76 mL, 435.9 mmol) followed byN-phenylbis(trifluoromethanesulfonamide) (40.1 g, 112.2 mmol). Thereaction was stirred at room temperature overnight. The solvent wasremoved under reduced pressure and the residue dissolved in 4:1 ethylacetate:hexane (500 mL total). The organic phase was washed with water(6×500 mL) and dried (MgSO₄). Filtration and removal of the solventunder reduced pressure gave4R,4aS,7aR,12bS)-4a-hydroxy-7-oxo-3-phenethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate(57.0 g, 109.0 mmol, 100% yield) as an orange oil.

4R,4aS,7aR,12bS)-4a-hydroxy-7-oxo-3-phenethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate(6.26 g, 12.0 mmol) was stirred in degassed DMSO (80 mL).N-hydroxysuccinimide (2.76 g, 24.0 mmol) was added followed bytriethylamine (3.34 mL, 24.0 mmol), palladium acetate (269 mg, 1.2 mmol)and xantphos (693 mg, 1.2 mmol). The reaction mixture was stirred at 70°C. under an atmosphere of CO overnight. The mixture was allowed toreturn to room temperature before the addition of5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (2.0g, 8.0 mmol) and triethylamine (1.7 mL, 12.0 mmol). The reaction wasstirred for 3 hours before removal of the DMSO under reduced pressure.The residue was subject to column chromatography (0 to 3% MeOH(NH₃) inDCM). The organic phases were combined and the solvent removed underreduced pressure giving(5a)-N-{2-[4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-14-hydroxy-6-oxo-17-(2-phenylethyl)-4,5-epoxymorphinan-3-carboxamide(Compound-18; 4.7 g, 7.4 mmol, 62% yield).

To a solution ofN-{2-[4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-14-hydroxy-6-oxo-17-(2-phenylethyl)-4,5-epoxymorphinan-3-carboxamide(Compound-18) (4.7 g, 7.4 mmol) in acetic acid (200 mL) was added zincpowder (14.6 g, 223 mmol) followed by concentrated HCl_((aq)) (8 mL).The reaction was heated at 90° C. for 1 hour after which time furtherzinc powder (14.6 g) was added. The reaction was maintained at the sametemperature for an additional 2 hours. The reaction mixture was allowedto cool and filtered. The zinc residue was washed with further aceticacid (100 mL). The combined acetic acid solutions were concentratedunder reduced pressure. The residue was basified with ammonium hydroxidesolution (28%) and the precipitated solid isolated by filtration. Theprecipitate was washed with water and dried overnight in a dessicator.The material was purified by prep-HPLC to give Compound 2N-{2-[4-(2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-4,14-dihydroxy-6-oxo-17-(2-phenylethyl)morphinan-3-carboxamide(1.17 g, 1.85 mmol, 25% yield) as a white solid; LC/MS 635 (M+H)⁺;NMR(DMSO-D₆): 502-133-9_1H-3.jdf: 1.40-1.50 (1H, m), 1.60-1.70 (2H, m),1.78-1.95 (3H, m), 2.50-2.58 (2H, m), 2.59-2.67 (3H, m), 2.68-2.77 (3H,m), 2.78-2.90 (4H, m), 2.91-3.20 (2H, m), 3.77 (1H, d), 4.30 (1H, s),6.61 (1H, d), 7.10-7.32 (7H, m), 7.44 (2H, d), 7.54 (2H, d), 8.91 (1H,t), 11.07 (1H, bs), 11.20 (1H, bs), 13.94 (1H, bs).

Example 15 Determination of Binding Affinities for Mu, Delta and KappaReceptors

Receptor Binding (in vitro Assay) The K_(i) (binding affinity) for μ-,δ-, and κ-receptors was determined with a previously described methodusing a competitive displacement assay (Neumeyer, 2003). Membraneprotein from CHO (Chinese Hamster Ovarian) cells that stably expressedone type of the cloned human opioid receptor were incubated with 12different concentrations of the compound in the presence of 0.25 nM[3H]DAMGO, 0.2 nM [3H]naltrindole or 1 nM [3H]U69,593 in a final volumeof 1 mL of 50 mM Tris-HCl, pH 7.5 at 25° C. Incubation times of 60 minwere used for [3H]DAMGO and [3H]U69,593. Because of a slower associationof [3H]naltrindole with the receptor, a 3 h incubation was used withthis radioligand. Samples incubated with [3H]naltrindole also contained10 mM MgCl₂ and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecificbinding was measured by inclusion of 10 μM naloxone. The binding wasterminated by filtering the samples through Schleicher & Schuell No. 32glass fiber filters using a Brandel 48-well cell harvester. The filterswere subsequently washed three times with 3 mL of cold 50 mM Tris-HCl,pH 7.5, and were counted in 2 mL Ecoscint A scintillation fluid. For[3H]naltrindole and [3H]U69,593 binding, the filters were soaked in 0.1%polyethylenimine for at least 60 min before use. IC₅₀ values will becalculated by least squares fit to a logarithm-probit analysis. Kivalues of unlabeled compounds were calculated from the equationKi=(IC50)/1+S where S=(concentration of radioligand)/(Kd of radioligand)(Cheng and Prusoff, 1973).

Example 16 Functional Activity (GTPγS Binding)

The [³⁵S]GTPγS assay measures the functional properties of a compound byquantifying the level of G-protein activation following agonist bindingin studies using stably transfected cells, and is considered to be ameasure of the efficacy of a compound. Membranes from CHO (ChineseHamster Ovary) cells that stably expressed the cloned human Mu opioidreceptor were used in the experiments. In a final volume of 0.5 mL, 12different concentrations of each test compound were incubated with 7.5μg of CHO cell membranes that stably expressed the human μ opioidreceptor. The assay buffer consisted of 50 mM Tris-HCl, pH 7.4, 3 mMMgCl₂, 0.2 mM EGTA, 3 μM GDP, and 100 mM NaCl. The final concentrationof [35S]GTPγS was 0.080 nM. Nonspecific binding was measured byinclusion of 10 μM GTPγS. Binding was initiated by the addition of themembranes. After an incubation of 60 min at 30° C., the samples werefiltered through Schleicher & Schuell No. 32 glass fiber filters. Thefilters were washed three times with cold 50 mM Tris-HCl, pH 7.5, andwere counted in 2 mL of Ecoscint scintillation fluid. Data are the meanEmax and EC50 values±S.E.M. For calculation of the Emax values, thebasal [35S]GTPγS binding was set at 0%, and the 100% [35S]GTPγS bindinglevel was set at the maximum binding achieved with DAMGO. Compounds inTable D show [35S]GTPγS binding EC50 values between 1.3 nM and 300 nMwith Emax values between 70% and 140%.

Example 17 In Vivo Behavioral Studies

Groups of mice (n=5 per group; >60 days; 20-25 grams weight) were dosedwith vehicle (0.9% sterile saline) or test compounds (10 mg/kg freebase, SC) 30 minutes before the first observation period. The occurrenceof Straub tail, piloerection, hyperlocomotion, hypolocomotion, circlingof the cage, sedation, breathing abnormalities, diuresis, seizureactivity and occurrences of death were recorded at 0.5, 1, 2, 4, 6 and24 hours following dosing.

The data below shows peripheral restriction for a series of compounds.This is tested with our clinical observation assay where mice areinjected with 10 mg/kg subcutaneously with drug and the behaviors arenoted over 24 hours. At the 10 mg/kg SC dose both morphine (Compound-A)and Compound-B show severe effects that reflect mu agonism in the brain,with observed mortality in the Compound-B group. In the heteroarylcompounds tested the behavioral effects and mortality was not observed.

The binding affinities of Compounds 1-11 are given in Table D

TABLE D Clinical In vitro Observations functional after 10 mg/kg agonismfor subcutaneous Binding affinity μ receptor No Compound injection μ(K_(i), nm) κ (K_(i), nm) δ (K_(i), nm) Agonist?  A

Multiple central nervous system like effects: Straub tail,hyperlocomotion, circling 0.32 230 11 Yes  B

Angioedema; Straub tail, hypolocomotion, mortality 0.39 0.71 5.4 Yes  1

None 27 850 490 Yes  2

None 0.66 >1 μM 24 Yes  3

None 0.63 180 17 Yes  4

None 1.3 190 >1 μM Yes  5

None 1.7 680 51 Yes  6

None 3.5 1000 97 Yes  7

None 0.52 860 42 Yes  8

None 0.15 19 2.1 Yes  9

None 1.7 400 280 Yes 10

None 0.43 140 10 Yes 11

None 1.6 >1 μM Yes

Example 18 CFA Induced Weight Bearing Deficits in Rats

Animals were habituated to the weight bearing test apparatus for 2 daysprior to the start of the experiment. On Day 0, rats were tested in theweight bearing apparatus to measure baseline weight bearing of untreatedhind paws. Following baseline testing, animals were injectedintra-plantar with Complete Freund's Adjuvant (CFA). Using a syringewith a locking hub and 25 G needle, rats were injected via rear, leftintra-plantar administration with 100 μl of 100% CFA (1.0 mg/ml) whileunder light isofluorane anesthesia. No treatment was administered to theright, rear, contralateral paw.

The treatment with morphine or Compound 4 (Intra-articular) was givenafter at the onset of arthritis in CFA treated rats (Day 1).Intra-plantar test-compound administration was done while the animal wasunder light (3%) isofluorane anesthesia using 0.3 ml insulin syringe.The amount of anesthesia given to the animal during test compoundadministration was limited to a very short duration, so not to impedemeasurement of weight bearing at the 5 minute time point. On Day 1 (24hrs. post CFA), rats were tested in the weight bearing apparatus tomeasure CFA-induced changes in weight bearing. Following testing,animals were injected intra-plantar with test compound (morphine orCompound 4) in a total volume of 50 μl containing 3, 10 or 100 μg doses.The inhibitory effect of naloxone on the analgesic effects of Compound 4and morphine (10 μg/paw) was tested by concurrent intra-plantaradministration of 75 ug naloxone methiodide, a peripherally restrictedopioid antagonist. Following test compound administration, animals wereretested in the weight bearing apparatus at the following time points:5, 15, 30, 60 and 120 minutes post-test compound administration. Animalswere retested on Day 2 (post—CFA) if there is a significant change inCFA induced weight bearing at the 120 minute time point on Day 1.

The administration (intra-plantar) of Compound 4 produced adose-dependent reversal of CFA-induced weight bearing deficits at 3, 10and 30 μg/paw. The analgesic effects of Compound 4, was comparable tothat seen with Morphine (FIGS. 1 and 2). The analgesic effects ofCompound 4 or Morphine (10 μg/paw) are significantly inhibited byconcurrent intra-plantar administration of 75 ug naloxone methiodide, aperipherally restricted opioid antagonist. The blockade of analgesia byintraplantar naloxone methiodide administration is suggestive ofperipheral analgesic effects of Compound 4 and morphine.

Example 19 Rat Hot Plate Model of Centrally Mediated Analgesia

The potential antinociceptive properties of subcutaneous (SC)administration of Compound 4 were assessed at doses of 10, 30, and 100mg/kg in the rat hot plate test of antinociception. Morphine (used as areference compound) produced maximal (60 sec) antinociception whenadministered SC at 7.5 mg/kg (shown here, and in previous in-houseexperiments).

Rats were tested for a baseline hot plate response (latency time for apaw on a hot plate set to 52.5° C.) immediately prior to dosing withCompound 4 or morphine (7.5 mg/kg) by SC injection. Rats were thentested on the hot plate 5, 30, 60, 120, 240 and 360 minutes later. Theamount of time it took to lick one hind paw is measured and isconsidered the response latency. The mean and SEM of the responseslatencies for each experimental group were calculated and a linedepicting mean hot plate latency vs. time was generated using GraphPadPrism. An increase in mean response latency above baseline followingtest compound administration is indicative of an antinociceptive effect.

Compound 4 was significantly less active than morphine in hot plate,with sub-maximal efficacy at the highest dose tested (100 mg/kg),suggesting significant peripheral restriction of Compound 4 (FIG. 3).

Example 20 Formalin Model of Pain

Nonfasted male Harlan rats were assigned to treatment group according toa randomized block study design to balance for test chamber and time ofday, and day of test (if applicable). Each rat was administered eithervehicle or test compound subcutaneously and then placed in theirassigned test chamber and acclimated for 25-30 minutes with the chamberenclosure door left open. Data was not collected during this period.Following the acclamation period, each rat was removed individuallystarting with chamber 1, and dosed 5% formalin subcutaneously into theright rear paw plantar surface (formalin was made from a 37% stocksolution, diluted down to 5% with saline).

Data collection started when the first rat was replaced in chamber 1 andthe chamber door was closed and latched (skipped 1-minute acclamationscreen on software). The number of events (also defined as “number ofseconds”), defined as the number of 1-second bins with a change indynamic force that exceeded an empirically determined threshold value (avalue of arbitrary load units, which corresponded visually with ratsquietly breathing or sniffing), were totaled in 5-minute intervals. Incontrol rats, the number of events first increases within 5 minutes andthen decreases during the subsequent 5 minutes (a quiescent phase) afterformalin administration (Phase I, or Early Phase, of the formalin test),then increases again during the subsequent 35 minutes (Phase II, or LatePhase) of the formalin test. Formalin-induced movements detected by thesystem include licking and flinching of the affected paw as well ashopping and turning.

For constructing summaries for analysis of dose response curves orscreens in the formalin test, the total number of events during thefirst 5 minutes after formalin administration was considered to be PhaseI (Early Phase), and the total number of events for minutes 11 to 35after formalin was considered to be Phase II (Late Phase). Data wereanalyzed using 1-way ANOVA, and comparisons of drug treatment groupswere compared with control groups using appropriate, statistician-guidedtests—most commonly Dunnett's for dose response curves and a Student'st-test for two-group (i.e., vehicle vs. positive control)comparison—utilizing JMP statistical software (SAS Institute Inc., Cary,N.C.). Data was expressed as means±SEM. An ED₅₀ was calculated utilizingGraphPad Prism software.

Subcutaneous administration of Compound 4 produced a dose-dependentreversal of formalin-induced events. The antinociceptive (analgesic)effects of Compound 4 (ED₅₀ 3.62 mg/kg) were comparable to morphine(ED₅₀ 2.4 mg/kg). As shown in FIG. 4, a 10 mg/kg dose of morphinecompletely mitigates both the early and late phase effects of formalin,suggesting both a centrally mediated (Early Phase) and peripherallymediated (Late Phase) effect on antinociception (analgesia). There is amore robust effect of Compound 4 in the Late Phase effects than theEarly Phase, suggesting a preferential, peripherally mediated effect onperipheral inflammatory pain.

Example 21 Acetic-Acid Induced Writhing Model of Inflammatory Pain

Intraperitoneal administration of morphine dose-dependently blockswrithing induced by the intraperitoneal administration of 1% acetic acidin mice with an ED₅₀ of 0.25 mg/kg. A dose response of the analgesiceffects of intraperitoneal administration of Compound 4 in the 1% aceticacid induced writhing assay in mice was measured.

Groups of mice (n=10 per group) were dosed intraperitoneally with avehicle control (0.9% saline), morphine or Compound 4, 30 minutes beforetesting followed by a dose of 1% acetic acid 5 minutes before testing.The number of writhes was counted for 15 minutes (3 consecutive 5 minutetime bins). In order for a movement to be considered a writhe, two ormore of the following criteria were met:

-   -   A perceivable concave curvature of the spine (termed a pelvic        tilt)—dorsal movement of the caudal spine region creating a        concave shape when viewed from the side; movement of the hips to        either the left or the right; or both.    -   A more severe concave spinal curvature was considered a vertical        writhe.    -   Abdomen made an effort to lower to the ground.    -   Hind legs, body, or both extended backwards and lengthened.    -   Tail flicked upward from base (does not typically occur separate        from pelvic tilt).    -   In the event of a chain of multiple writhes, the end of a        discrete writhe was determined when the mouse returned to        “normal” posture before writhing once again. “Normal” posture        was defined as movements opposite to those listed above (e.g.,        convex curvature of the spine, legs not extended, abdomen not        lowered, tail in a straight or relaxed position, etc).

The total number of writhes over the 15 minute test session was used forall data analysis. All data was transformed using GraphPad Prism to %change from daily vehicle control for analysis based on the number ofwrithes produced by the saline vehicle control group (% change=# writhesin test group/mean # of writhes in daily vehicle control group*100). AnED₅₀ of the % change from daily vehicle control was calculated formorphine and compound 4 utilizing GraphPad Prism software.

As shown in FIG. 5, administration (intraperitoneal) of Compound 4blocked acetic acid induced writhing in a dose-dependent manner with acalculated ED₅₀ of 0.7 mg/kg.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

The invention claimed is:
 1. A method for treating pain comprising thestep of administering a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or Formula II to a subject in need thereof:

Wherein: u is 0, 1 or 2; t is 0, 1, 2, 3, 4, 5, 6, or 7; X is S or O;Y^(⊖) is a pharmaceutically acceptable counterion; R₁ is selected fromaliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclylor substituted heterocyclyl; Each R₂, R₃, R₄, R₆, R₈, and R₁₁ isindependently selected from hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁,—C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃,acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,dialkylamino, substituted dialkylamino, alkylthio, substitutedalkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic,substituted aliphatic, aryl, substituted aryl, heterocyclyl orsubstituted heterocyclyl; alternatively R₂ and R₃ together with thecarbon they are attached to form a C═X group or a vinyl group;alternatively, two R₁₁ groups together with the carbon atom to whichthey are attached form a C═X or a vinyl group; wherein each R₂₀ and R₂₁is independently selected from hydrogen, halogen, alkyl, substitutedalkyl, aryl or substituted aryl; R₅ is alkyl, substituted alkyl, aryl orsubstituted aryl; R₇ is hydrogen alkyl, substituted alkyl, aryl orsubstituted aryl; R₉ is selected from hydrogen, aliphatic, substitutedaliphatic, aryl, substituted aryl, heterocyclyl or substitutedheterocyclyl; and R₁₀ is selected from Table A:

wherein s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; q is 0, 1,2, 3, 4, or 5; each R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, and R₁₀₅ isindependently selected from hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁,—C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —CF₃, —CN, —NO₂, —N₃,acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,dialkylamino, substituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, optionallysubstituted aliphatic, optionally substituted aryl, heterocyclyl orsubstituted heterocyclyl; wherein the term “substituted” refers to thereplacement of one or more hydrogen radicals in a given structure withthe radical selected from halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl,alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy,aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl,cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl,aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, heteroaryl,and aliphatic.
 2. The method according to claim 1, wherein said compoundis a mu receptor agonist.
 3. The method according to claim 1, whereinsaid pain is selected from inflammatory pain, centrally mediated pain,peripherally mediated pain, visceral pain, structural related pain,cancer pain, soft tissue injury related pain, progressive diseaserelated pain, neuropathic pain and acute pain from acute injury, acutepain from trauma, acute pain from surgery, chronic pain from headache,chronic pain from neuropathic conditions, chronic pain from post-strokeconditions and chronic pain from migraine.
 4. The method according toclaim 1, wherein said pain is associated with osteoarthritis, rheumatoidarthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn,snake bite, spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulitis, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis,migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidianneuralgia, inflammatory bowel disease, irritable bowel syndrome, sinusheadache, tension headache, labor, childbirth, menstrual cramps, andcancer.
 5. The method according to claim 1, wherein said pain isassociated with arthritis.
 6. The method according to claim 5, whereinsaid arthritis is selected from rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, juvenile arthritis,scapulohumeral periarthritis.
 7. The method according to claim 2,wherein the compound does not substantially cross the blood-brainbarrier.
 8. The method according to claim 1, wherein said compound ofFormula I is selected from:

or a pharmaceutically acceptable salt thereof.
 9. A method for treatingpain by modulating the activity of an opioid receptor(s) comprising thestep of administering a compound to a subject in need thereof whereinsaid compound is selected from:

or a pharmaceutically acceptable salt thereof.
 10. The method accordingto claim 1, wherein R₁₀ is selected from below:


11. The method according to claim 1, wherein R₁₀ is selected from thetable below:


12. The method according to claim 1, wherein said compound of Formula Iis selected from:

or a pharmaceutically acceptable salt thereof.